Use of 5-HT3 receptor antagonists for treating musculoeskeletal diseases

ABSTRACT

The present invention relates to a new use for compounds having 5-HT 3  (serotonin M) receptor antagonist activity, especially tropisetron, for the manufacture of a pharmaceutical composition for the treatment of a non-inflammatory local disease of the musculo-sceletal system, of a local irritation condition of a joint or tendon sheath, or for the local treatment a local manifestation at the locomotor apparatus of an inflammatory disease except for a crystal induced arthritis and a living pathogen induced inflammatory disease condition as long as the living pathogen is still present.

This application is a continuation of PCT Patent Application No.PCT/EP00/01269, filed Feb. 16, 2000, which is herein incorporated byreference.

The present invention relates to a new use, in particular a newpharmaceutical use for compounds having 5-HT₃ (serotonin M) receptor, inparticular specific 5-HT₃ receptor, antagonist activity, especially inthe manufacture of a pharmaceutical composition.

Specifically, the present invention relates to the treatments definedbelow.

The 5-HT₃-receptor antagonists comprise a defined and recognised classof pharmaceutically active compounds well known in the art andcharacterised, as their name implies, by their pharmacological activity.Various 5-HT₃ receptor antagonist compounds are commercially availableand clinically applied, e.g. in the treatment of emesis.

In accordance with the present invention it has now surprisingly beenfound that 5-HT₃ receptor antagonists are useful for the treatment oflocal non-inflammatory, local irritation-related and local inflammatorydisease conditions. This is surprising in that (a) the 5-HT₃ receptorantagonists are effective alone; (b) do not only bring pain relief, butalso are effective in the treatment of other symptoms, such as effusion,swelling, stiffness and the like, and (c) are locally effective, thusnot having to rely on systemic administration that may show effects e.g.by working via effects on nerves and/or synapses at the spinal cord. Itis also astonishing that relatively high local doses are both toleratedand effective when local administration is employed.

Hence, the present invention relates to the use of a 5-HT₃ receptorantagonist or of a pharmaceutically acceptable salt of such anantagonist for the manufacture of a pharmaceutical composition for thetreatment of a non-inflammatory local disease of the musculo-sceletalsystem, of a local irritation condition of a joint or tendon sheath, orfor the local treatment a local manifestation at the locomotor apparatusof an inflammatory disease except for a crystal induced arthritis and aliving pathogen induced inflammatory disease condition as long as theliving pathogen is still present for example the treatment of anyprocess, condition, event, or disease as hereinafter described. Inparticular, the present invention provides the use as mentioned beforewhere, in addition to pain at least one further sequela or symptom ofthe local disease, local irritation condition or local manifestation isalleviated, ameliorated or controlled.

Any 5-HT₃ receptor antagonist can be used in accordance with theinvention. Preferred 5-HT₃ receptor antagonists which may be employed inaccordance with the present invention are:

A) Ondansetron[1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl]methyl]-4H-carbazol-4-one(cf. Merck Index, twelfth edition, item 6979);

B) Granisetron[endo-1-methyl-N-(9-methyl-9-aza-bicyclo[3.3.1]non-3-yl)-1H-imidazole-3-carboxamide:(cf. loc. cit., item 4557); and

C) Dolasetron [1H-indole-3-carboxylic acid (2α, 6α, 8α,9αβ)-octahydro-3-oxo-2,6methano-2H-quinolizin-8-yl ester] (cf. loc.cit., item 3471).

Particular 5-HT₃ receptor antagonists which may be employed inaccordance with the present invention are those of the formula 1 asdefined in European Patent Publication 189002 B1, the contents of whichare incorporated herein by reference, in particular the compound:

D) Indol-3-yl-carboxylicacid-endo-8-methyl-8-aza-bicyclo[3,2,1]-oct-3-yl-ester, also known astropisetron. (cf. loc.cit., item 9914).

Further 5-HT₃ receptor antagonists which may be used preferably inaccordance with the present invention are:

E) 4,5,6,7-tetrahydro-5-[(1-methyl-indol-3-yl)carbonyl]benzimidazole(see also ramosetron, see U.S. Pat. No. 5,344,927);

F)(+)-10-methyl-7-(5-methyl-1H-imidazol-4-ylmethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one(see also fabesetron, EP 0 361 317); and

G)[N-(1-ethyl-2-imidazolin-2-yl-methyl)-2-methoxy-4-amino-5-chlorobenzamide(see also lintopride-Chem.-Abstr.-No. 107429-63-0).

A further 5-HT₃ receptor antagonists which may be used preferably inaccordance with the present invention is

(H)2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one(see also alosetron, EP 0 306 323).

5-HT₃-receptor antagonists may be employed in accordance with theinvention in free or in pharmaceutically acceptable salt form, e.g. asknown in the art, for example, in the case of compounds A) to D) abovein pharmaceutically acceptable acid addition salt form, for example, inthe case of: compound A) the hydrochloride dihydrate; compound B) thehydrochloride; compound C) the mesylate; and compound D) themonohydrochloride. References to 5-HT₃ receptor antagonists collectivelyor individually throughout the present specification and claims areaccordingly to be understood as embracing both free compounds and suchpharmaceutically acceptable salt forms, e.g. as clinically employed, andfurther also solvates, e.g. hydrates, or specific crystal forms of anyof these compounds or salts.

For use in accordance with the present invention tropisetron (especiallyin the formulation called NAVOBAN®) is most preferred.

Thus, the invention relates to the use of a 5-HT₃ receptor antagonist orof a pharmaceutically acceptable salt of such an antagonist for themanufacture of a pharmaceutical composition for the treatment of anon-inflammatory local disease of the musculo-sceletal system, of alocal irritation condition of a joint or tendon sheath, or for the localtreatment a local manifestation at the locomotor apparatus of aninflammatory disease except for a crystal induced arthritis and a livingpathogen induced inflammatory disease condition as long as the livingpathogen is still present, where the 5-HT₃ receptor antagonist isselected from the group consisting of ondansetron, granisetron,dolasetron, tropisetron, ramosetron, fabesetron, lintopride andalosetron, which may be used in free form or as a pharmaceuticallyacceptable salt.

In accordance with the present invention it has now surprisingly beenfound that 5-HT₃ receptor antagonists are useful for the treatment ofcertain diseases, processes, conditions or events, namelynon-inflammatory local diseases of the musculo-sceletal system; localirritation conditions of the joints or tendon sheaths; or the localtreatment also of local manifestations at the locomotor apparatus ofinflammatory diseases; such as conditions, processes or events that aredue to trauma (including surgery or preferably accident); overload;posture fault; degenerative processes; conditions subsequent to anotherdisease (including infection, for example viral infection, or tumordiseases); or other conditions that result in irritation of thelocomotor apparatus of the body; meaning especially therapy of therespective non-inflammatory disease, irritation or manifestation assuch, its sequelae or its symptoms, or any combinations of these.

“Treatment” as used herein includes use for the alleviation,amelioration or control of said diseases, processes, conditions orevents. It also includes intervention for the alleviation, ameliorationor control of the sequelae or symptoms of any one or more of thesediseases, for example degeneration (e.g. of cells, epithelia ortissues), swelling, exudation, effusion or pain, stiffness orinflexibility of joints. In this context the term “treatment” is furtherto be understood as embracing use to reverse, restrict or controlprogression of any specified disease, process, condition event or thelike, including use for disease modifying effect. If any of thementioned diseases, processes, conditions, manifestations or events,especially an inflammatory disease, process, condition, manifestation orevent, is associated with pain, the term “treatment” preferablyencompasses the alleviation, amelioration or control (including temporalor permanent removal) of at least one further sequela or symptom inaddition to pain, such as swelling, effusion, exsudation, lack offlexibility (e.g. due to stiffness and/or lack of flexibility ofjoints), loss of strength or degeneration, more preferably of allsymptoms and most preferably of the total clinical picture of therespective disease, irritation or manifestation. According to thepresent invention, the term “treatment” preferably does not have themeaning of prevention.

The present invention is in particular applicable to the treatment of:

(1) non-inflammatory local diseases of the musculo-sceletal system(including a joint or another part of the locomotor apparatus), such as

(1a) myofasciale syndrome, including myelogelosis, chronic lumbalgia orcervicalgia, for example unspecific or in the context of degenerativespinal affections, of static posture fault or malformation of the spine,e.g. cervical syndrome,

(1b) tendomyosis, tendinosis, insertion tendopathy (e.g. epicondylitis),bursopathy or peri-arthropathy,

(1c) overload syndrome of the muscle,

(1d) syndromes due to the compression of nerves or neuropathy (such asmedianus compression syndrome=carpal tunnel syndrome), or

(1e) algodystrophy (also called neurodystrophy); or

(2) local irritation conditions (=states of irritation) of a joint ortendon sheath especially related to

(2a) a meniscus lesion (e.g. following surgical intervention orpreferably due to damage to the meniscus due to a different cause),

(2b) arthrosis, such as gonarthrosis,

(2c) trauma, including accident or post-operative trauma, e.g. afterimplant or insertion surgery or endoscopy,

(2d) osteochondritis dissecans, osteonecrosis or joint chondromatosis,

(2e) or various non-inflammatory rheumatoid diseases, preferably to thelocal treatment of one or more of the mentioned diseases under (1)and/or (2); or

(3) to the local treatment also of a local manifestation at thelocomotor apparatus of an inflammatory disease, such as variousinflammatory rheumatoid diseases (except for crystal induced arthritis(e.g. gout) and except for living pathogen induced diseases as long asthe living pathogen (bacterium, virus or fungus, protozoon, parasite orthe like) is still present), such as

(3a) chronic polyarthritis (=rheumatoid arthritis), including juvenilearthritis or psoriasis arthropathy;

(3b) sarcoidosis,

(3c) paraneoplastic syndrome or tumor-induced inflammatory diseases,

(3d) turbid effusions,

(3e) collagenosis, such as systemic Lupus erythematosus, poly-myositis,dermato-myositis, systemic sclerodermia or mixed collagenosis;

(3f) postinfectious arthritis (where no living pathogenic organism canbe found at or in the affected part of the body), or

(3g) seronegative spondylarthritis, such as spondylitis ankylosans; orfurther

(3h) vasculitis.

In the case of the inflammatory diseases, diseases where a livingpathogen, e.g. a virus, a bacterium, a fungus, a protozoon or a parasiteor the like, is still present, the treatment of must first aim atremoval of the pathogen causative for the disease, before treatment witha 5-HT₃ antagonist is used, as otherwise there is the danger that thecausative pathogen remains intact. Then the mere symptomatic treatmentwith a 5-HT₃ antagonist is contraindicated in order to avoid survival oreven further spread of the causative infection. This is also valid inthe case of combination with an anti-inflammatory glucocorticosteroid asdescribed in the following, as is the proviso that treatment ofcrystal-induced inflammation is excluded.

The term “locomotor apparatus” refers to any component of themusculo-sceletal system of the body, especially to bony tissue, muscle,tendons, ligaments, joints, cartilage, perichondrium, periosteum,synovial membrane, bursa and the like.

“Trauma” refers preferably to operative and more preferably to trauma byaccident, such as overload, tumble or push.

The term “local treatment” refers to the treatment with one or more5-HT₃ receptor antagonists near or at the site of the manifestation ofthe disease to be treated, e.g. by intra-muscular injection,intra-articular injection, or any other injection near or at the site ofdisease manifestation (that is, preferably the administration has thegoal to provide for locally higher concentrations of the administeredcompound than would be expected to be achieved by systemicadministration, or the goal is not systemic exposure), preferably withinan area within 20, more preferably 10 cm, still more preferably within 5cm, around the outer limitation of the manifestation of the localdisease, most preferably directly at the affected are or site, e.g. theare or site of symptom manifestation, such as the area of greatest pain,such as an insertion point, a trigger point or a joint, or also in abroader aspect of the invention by local tissue infiltration ortransdermal administration at the site of the manifestation of thedisease, e.g. by means of topical administration e.g. by use of gels,creams or ointments or the like, or by transdermal patch technology. Inthe case of the non-inflammatory diseases mentioned above under (1) and(2), also systemic treatment is possible, e.g. by enteral, especiallyperoral, e.g. by use of tables or capsules, or rectal, e.g. by use ofenemation or suppositories; subcutaneous, intraperitoneal orintra-muscular injection; or infusion is possible. In the case ofintravenous administration bolus injection is preferred. However, localtreatment is preferred in all cases. An advantage of local treatment isthat high efficiency can be reached and that systemic exposure to a5-HT₃ antagonist can be diminished or avoided. One preferred local wayof administration is the intra-articular injection in case of diseases,conditions etc. that relate to joints, e.g. bursopathy or synovitis.

A preferred example of a local manifestation at the locomotor apparatusof an inflammatory disease is synovial inflammation, for example,synovitis, including any of the particular forms of synovitis recited inDorland's Illustrated Medical Dictionary, 26th edition, pub. W. B.Saunders and Co. at page 1301, as far as it is not crystal-induced. Suchsynovial inflammation may for example, be consequential to or associatedwith disease, e.g. arthrosis, including arthritis, e.g. osteoarthritis,rheumatoid arthritis or arthritis deformans.

Further preferred local diseases to be treated according to theinvention are those mentioned in the examples.

From the foregoing it will be noticed that the present invention is tobe understood especially as embracing the treatment, e.g. therapy, ofany disease, process, symptom, event or condition as set forth above,for example for the alleviation or control of non-inflammatory localdiseases or irritations or local inflammatory processes or events andthe sequelae associated therewith or consequential thereto, e.g. toalleviate or control joint irritation or effusion; with the proviso thatif pain is treated, then in addition at least one other diseasemanifestation (e.g. effusion, swelling, exudation or degeneration) istreated.

Preferably the present invention relates to the treatment, especiallythe local treatment, of a disease as mentioned above under (2) or (3),more preferably one of the diseases mentioned there other thanalgodystrophy and vasculitis.

In a further aspect it has been found in accordance with the presentinvention that 5-HT₃ receptor antagonists are useful as replacementtherapy for local glucocorticosteroid, e.g. cortisone or the like,therapy; for example for use in any means of treatment as hereinbeforeand hereinafter set forth, e.g. the diseases mentioned under (2) and (3)hereinabove.

The term “replacement therapy” as used herein is to be understood asembracing both use “as full replacement”, i.e. use instead ofglucocorticosteroid therapy, as well as use “as partial replacement” forglucocorticosteroid therapy, i.e. for administration together withglucocorticosteroid therapy or as a means of reducingglucocorticosteroid dosage or to achieve a glucocorticosteroid sparingeffect.

The present invention accordingly provides:

I. A method of treating any process, condition, event, or disease ashereinbefore set forth, in a subject in need thereof, which methodcomprises locally administering an effective amount of a 5-HT₃ receptorantagonist, especially locally at or near the site of the local disease,local irritation condition or local manifestation;

II. A method of providing replacement therapy for glucocorticosteroidtherapy in a subject receiving such glucocorticosteroid therapy for orin the treatment of any process, condition, event or disease ashereinbefore set forth, which process comprises locally administering tosaid subject an effective amount, e.g. a glucocorticosteroid sparingamount, of a 5-HT₃-receptor antagonist; as well as

III. A method of treating any process, condition, event or disease ashereinbefore set forth, in a subject in need thereof, which methodcomprises locally administering an effective amount of a 5-HT₃ receptorantagonist together with a glucocorticosteroid.

Where the term “glucosteroid” is used, this means an anti-inflammatoryglucosteroid.

Where co-administration is practiced as under III above the drugsubstances, i.e. 5-HT₃ receptor antagonist and glucocorticosteroid maybe administered sequentially or simultaneously or substantiallysimultaneously, e.g. employing a fixed combination dosage form.

In further aspects the present invention also provides:

IV. A 5-HT₃ receptor antagonist for use in, or for use in themanufacture of a pharmaceutical composition for use in; or the use of apharmaceutical composition comprising a 5-HT₃ receptor antagonist forlocal use:

a) in the treatment of any process, condition, event or disease ashereinbefore set forth;

b) as replacement therapy for glucocorticosteroid therapy in thetreatment of any process, condition, event or disease as hereinbeforeset forth; or

c) for co-administration together with a glucocorticosteroid in thetreatment of any process, condition, event or disease as hereinbeforeset forth; and/or:

V. A pharmaceutical dosage form comprising a 5-HT₃ receptor antagonisttogether with a glucocorticosteroid, especially for the local treatmentof any process, condition, event or disease as hereinbefore set forth.

Where under (I) to (V) the term “any process, condition, event ordisease” is used, this term preferably relates to the diseases mentionedunder (1), (2) and (3) above, especially as defined above as beingpreferred.

The term “locally administering” or “local use” is defined to mean localadministration or especially “local treatment” as defined above, thatis, administration at or near the site of the non-inflammatory disease,irritation condition or local inflammatory disease condition, incontrast to systemic administration.

Dosage forms, e.g. in accordance with V above, are to be understood asincluding both fixed-unit-dosage forms, e.g. liquid formulations,comprising both active ingredients together with appropriatepharmaceutically acceptable diluents or carriers, as well as twindelivery systems, packages or the like comprising both activeingredients separately or in separate dosage form, for concommitant orsequential administration.

The 5-HT₃ receptor antagonists are preferably used in well-known liquidformulations.

Utility of 5-HT₃ receptor antagonists in accordance with the presentinvention can be demonstrated in clinical trials carried out inaccordance with standard techniques and methodologies, for example asfollows:

The following examples are for illustrative purposes and are notintended to diminish the scope of the present invention. Instead oftropisetron, any other 5-HT₃-antagonist, or a pharmaceuticallyacceptable salt thereof, solvate, e.g. hydrate, or crystalline formthereof, especially selected from the group consisting of ondansetron,granisetron, dolasetron, ramosetron, fabesetron, lintopride andalosetron, can be used, or any combination of two or more of these 5-HT₃receptor antagonists or pharmaceutically acceptable salts thereof.

In the following examples, tropisetron is administered in the standardformulation of the trademark Navoban® which is available in ampoulesthat contain 2 mg or 5 mg of the active substance, tropisetron.

EXAMPLE 1 Treatment of Synovial Inflammation/Synovitis Consequent toInflammatory Processes

Trials are performed on 2 patients exhibiting rheumatoid arthritis andsevere consequential synovial inflammation as well as marked pain.

Two patients exhibiting acute exacerbation of rheumatoid arthritis, onein the shoulder joint, the other in the knee joint, are each treatedonce with 2 mg tropisetron administered intra-articularly. In both casestreatment leads to almost complete remission from pain within a fewhours. Both patients are examined over a period of one week followingtreatment with tropisetron and are found to be free of symptoms.

EXAMPLE 2 Treatment of Synovial Inflammation Following Traumatic orDegenerative Event

A first patient exhibits repeated exudation from the knee jointconsequential to damage to the meniscus. Prior to the trial the patientreceived injections of glucocorticoid. The patient receives an injectionof 2 mg of tropisetron administered intra-articularly. After 45 min.marked reduction of pain is reported and a major reduction of effusionfrom the knee joint is observed after 5 hours. The patient remains freeof symptoms without further therapy over an observation period of 5days.

A second patient exhibits damage to the meniscus of the right knee jointas well as arthritic change leading to synovial irritation withconsequential knee joint effusion. Despite a successful synovialectomyprior to trial entry the patient exhibits renewed knee joint effusion.Two 2 mg doses of tropisetron are administered i.v. over a period of 17days with 15 injections, one each day with a 2 days pause in therapy. 24hours after the first i.v. injection, significant improvement of pain isreported. Following continuation of injections, the patient exhibits asvirtually free of symptoms. The exudation from the knee joint iscompletely inhibited without any other medication within 8 days andmovement of the knee joint is clearly improved. The improvement incondition continues over a further 7 days observation followingcompletion of therapy:

EXAMPLE 3 Treatment of Implant or Insertion Tendopathy

Three patients exhibiting implant/insertion tendopathy are treated withtropisetron. The condition treated results in the case of the firstpatient from epicondylitis radialis, in the case of the second patientfrom insertion tendopathy in the area of insertion of the deltoid muscleand, in the case of the third patient from an enthesiopathy of theMalleolus lateralis. In all three cases, tropisetron is injected once ata dosage of 2 mg in the area of greatest pain, directly into thetissues. In all three cases severity of pain decreases within a periodof 60 min. and virtually complete remittal is achieved within 24 hrs.,indicating remission from disease remission. Further improvements foundafter tropisetron injection include increase of strength and offlexibility of the affected body part.

EXAMPLE 4 Further Examples for the Efficiency of Tropisetron

Pain is subsequently determined on a visual analogue scale (VAS) thatgoes from 0 mm (no pain) to 100 mm (strongest pain).

4a) Enthesiopathy (Insertion Tendopathy) (with infiltration)

(i) Female patient, born in 1955; Diagnosis: epicondylitis. Rest painbefore local injection of tropisetron 30 mm, 7 days later 0 mm.

(ii) Female patient, born 1947, diagnosis: periarthropathiahumeroscapularis. Rest pain before local injection of tropisetron 85 mm,7 days after local injection 45 mm.

(iii) Patient born 1953, diagnosis: epicondylitis. Rest pain beforelocal injection of tropisetron 35 mm, 7 days thereafter 0 mm.

4b) Rheumatoid arthritis (intraarticular injection)

(i) Female patient, born 1942.

Before injection of Navoban into the right knee joint: rest pain 62 mm,pain under exercise 82 mm, bending up to 105°, knee joint circumference46 cm. 24 hours later: rest pain 22 mm, pain under exercise 21 mm,bending 105°, knee joint circumference 45 cm. 48 hours after treatment:rest pain 0, pain under exercise 5 mm, bending 110°, knee jointcircumference 45 cm. 7 days after treatment: rest pain 20 mm, pain underexercise 16 mm, bending up to 145°, knee joint circumference 45.4 cm.

(ii) Female patient, born 1947.

Before injection of 2 mg Navoban into the left knee joint: rest pain 25mm, pain under exercise 85 mm, bending up to 115°, knee jointcircumference 37.5 cm. 24 hours later: rest pain 8 mm, pain underexercise 58 mm, bending 120°, knee joint circumference 37.5 cm. 48 hoursafter treatment: rest pain 6 mm, pain under exercise 55 mm, bending115°, knee joint circumference 37.5 cm. 7 days after treatment: restpain 5 mm, pain under exercise 59 mm, bending up to 115°, knee jointcircumference 37 cm. Now 5 mg Navoban are injected into the knee joint,7 days later the patient has a rest pain of 0 mm, pain under exercise of33 mm, bending is possible up to 120°, and the knee joint circumferenceis 37.5 mm.

4c) Treatment of left knee joint irritation (Morbus Still)

Patient, 26 year old, Morbus Still diagnosed 1.5 years ago. Despitebasic treatment with 15 mg methotrexat per week and 20 mg prednisoloneper day, the patient suffers from swelling and overheating of the leftknee joint for the first time in February 1999. Pain at rest in the VAS98 (0-100), pain under strain 70. Obvious articular effusion. Knee jointcircumference 44 cm, straightening/bending 0°-10°, 115°. 24 hours afteran intraarticular injection with 2 mg tropisetron pain at rest in theVisual Analog Scale (VAS) 0, pain under strain 70. Straightening/bending0°, 0°, 135°, knee joint circumference 41 cm, with significant reductionof joint swelling and effusion respectively. 7 days later pain at restin the VAS 0, pain under strain 57, straightening/bending 0°, 0°, 130°,knee joint circumference 40.5 cm.

4e) Gonarthrosis

Patient, 74 years old, has activated gonarthritis with effusion for 2months. Only short-term pain reduction by means of non-steroidalantiphlogistics could be achieved. Following an intra-articularinjection with 2 mg tropisetron, pain at rest after 24 hours on thevisual analog scale for pain (0-100) sinks from 43 to 25, after 2 daysto 13, after 7 days to 10 and in a follow-up check after 17 days to 4.The analog values for pain under strain are 75, 45, 10 and 10,respectively. The effusion is gone after 7 days, as is the overheatingof the knee joint.

EXAMPLE 5 Spinal Syndrome (i.v. Administration)

Female patient born 1957, diagnosis: cervical syndrome. Before injectionof 2 mg tropisetron 68 mm rest pain, 24 hours later 35 mm, at day 7 18mm.

EXAMPLE 6 Spinal Syndromes (i.v. Administration)

(i) Cervical Syndrome

Female patient born 1957, diagnosis: cervical syndrome. Before i.v.injection of 2 mg tropisetron 68 mm rest pain, 24 hours later 35 mm, atday 7 18 mm.

(ii) Lumbalgia

Patient born 1940, diagnosis: lumbalgia. The patient is injected 2 mgNavoban i.v., the rest pain before the injection amounts to 78 mm, thepain under exercise 90 mm, the Schober distance upright/with bendedupper part of the body between the processus spinalis vertebrae ofvertebra 1 and 5 (“Schober” hereinafter) 10/11 cm, the distance fromfingers to ground with bended upper part of the body 32 cm; 24 hourslater, the rest pain is 36 mm, the pain under exercise 43 mm, theSchober 10/12.3, and the finger/ground distance 24 cm; after 48 hours,the rest pain is 28 mm, the pain under exercise 47 mm, the Schober10/12.5, the finger/ground distance 26.5 cm. 7 days after treatment, therest pain is 15 mm, the pain under exercise 22 mm, the Schober 10/13,and the finger/ground distance 22 cm.

Equivalent results as in the preceding examples are obtainable inequivalent or comparable trials with patients exhibiting similarsymptomatology employing 5-HT₃-receptor antagonists other thantropisetron, for example using any of the 5-HT₃-receptor antagonists A)through C) or E) through H) hereinbefore recited at comparable, e.g.conventional clinical, dose as known in the art. Similar results arealso achievable employing 5-HT₃-receptor antagonists, e.g. tropisetronat doses of the order of 2 mg/day p.o. or by injection or topicalapplication in clinical trials involving subjects exhibiting other localnon-inflammatory or local inflammatory diseases, conditions or symptoms.

Trials conducted as described above or analogously are demonstrative oflong lasting and disease modifying effects in conditions hereindescribed as well as symptomatic and glucocorticosteroid replacementeffect for 5-HT₃ receptor antagonists.

For use in accordance with the present invention the appropriate dosagewill, of course, vary depending on for example the particular 5-HT₃receptor antagonist employed the mode of administration and the natureand severity of the condition to be treated as well as the specificcondition to be treated. In general an indicated single, e.g. daily,dosage will be in the range usually employed for known indications suchas emesis and will typically be from about 0.05 to about 50 mg per day,more preferably around 1 to 10 mg per day, conveniently administeredonce or in divided doses up to four times a day or in sustained releaseform, or used repeatedly after longer intervals, e.g. after some days orweeks, e.g. after 2 days to 4 weeks. In the case of tropisetron anappropriate dosage for administration, e.g. by injection, for examplefor i.v. application or injection direct into the affected areas, willbe of the order of 2 mg per day or 5 mg per day, administered once,sequentially over a sequence of 2 to 20 days or at intervals of 2 to 5days to 2 days to 2 weeks.

For use in accordance with the invention, 5-HT₃ receptor antagonists maybe administered by any conventional route in particular enterally,preferably orally, e.g. in the form of tablets or capsules, or rectally,e.g. in the form of suppositories or enemation, or most preferablyparenterally, e.g. in the form of injectible solutions or suspensions,e.g. by subcutaneous, intraperitoneal or intra-muscular injection forsystemic administration. Suitable formulations for use in accordancewith the present invention will include any of those as known andcommercially available and clinically employed in the art, for examplethe commerically available formulations. Preferably, the compositionsare administered locally, that is, near or at the site of themanifestation of the disease to be treated, e.g. by intramuscularinjection, intra-articular injection or any other injection near or atthe site of disease manifestation; in a broader aspect of the invention,also local tissue infiltration or transdermal administration may beconsidered, e.g. by use of gels, creams or ointments or the like, orpreferably by transdermal patches. Dosages for such forms will be of theorder or slightly higher than those used on administration by injection.

What is claimed is:
 1. A method of treating a non-inflammatory localdisease of the musculo-skeletal system selected from the groupconsisting of myofasciale syndrome, tendomyosis, tendinosis, insertiontendopathy, bursopathy or peri-arthropathy, syndromes due to thecompression of nerves and algodystrophy, in a subject in need thereof,which method comprises locally administering to said subject aneffective amount of a 5-HT₃ receptor antagonist.
 2. A method accordingto claim 1, wherein the 5-HT₃ receptor antagonist is administeredlocally at or near the site of the local disease, local irritationcondition or local manifestation.
 3. A method according to claim 1,wherein the 5-HT₃ receptor antagonist is tropisetron.
 4. The method ofclaim 1 wherein the 5-HT₃ receptor antagonist is selected from the groupconsisting of ondansetron, granisetron, dolasetron, tropisetron,ramosetron, fabesetron, lintopride and alosetron and pharmaceuticallyacceptable salts thereof.
 5. The method of claim 2 wherein the 5-HT₃receptor antagonist is selected from the group consisting ofondansetron, granisetron, dolasetron, tropisetron, ramosetron,fabesetron, lintopride and alosetron and pharmaceutically acceptablesalts thereof.